Is TGFB3 p.Ser375= (c.1125G>A) pathogenic?

TGFB3 p.Ser375= (c.1125G>A) is classified Likely benign in TGFB3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-12). Very rare (popmax 0.00891%, eas); Associated with Rienhoff syndrome.

What condition is associated with TGFB3 p.Ser375= (c.1125G>A)?

TGFB3 p.Ser375= (c.1125G>A) is associated with Rienhoff syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is TGFB3 p.Ser375= (c.1125G>A) in the general population?

TGFB3 p.Ser375= (c.1125G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

TGFB3 p.Ser375=

c.1125G>A · rs746094390 · VCV2075959

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Conditions

Rienhoff syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -3.7
Overall
CADD	0.514	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,878 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000372% 6/1,614,106 alleles · very rare exomes 6/1,461,864 · genomes 0/152,242 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,220
South Asian	0.0011%	91,080
European (non-Finnish)	8.47e-05%	1,180,008

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TGFB3
Protein: p.Ser375=
Coding: c.1125G>A
MANE Select: NM_003239
dbSNP: rs746094390
Type: single nucleotide variant
Location: chr14:75959301 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.48 · 11 PDB
Residue 375: an α-helix

Full TGFB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Rienhoff syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

TGFB3 p.Ser375Leu Uncertain significance ★★ ⚠ same residue
TGFB3 p.Ser375Ter Likely pathogenic ★ same residue
TGFB3 c.517-2A>G Likely pathogenic ★★ same condition
TGFB3 c.646+1G>C Likely pathogenic ★★ same condition
TGFB3 c.926+1G>A Likely pathogenic ★★ same condition
TGFB3 c.927-1G>C Likely pathogenic ★★ same condition
TGFB3 p.Arg148Ter Pathogenic/Likely pathogenic ★★ same condition
TGFB3 p.Arg300Gln Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tgfb3-p-ser375 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown